RESUMO
MUC1 is overexpressed and aberrantly glycosylated in more than 60% of pancreatic ductal adenocarcinomas. The functional role of MUC1 in pancreatic cancer has yet to be fully elucidated due to a dearth of appropriate models. In this study, we have generated mouse models that spontaneously develop pancreatic ductal adenocarcinoma (KC), which are either Muc1-null (KCKO) or express human MUC1 (KCM). We show that KCKO mice have significantly slower tumor progression and rates of secondary metastasis, compared with both KC and KCM. Cell lines derived from KCKO tumors have significantly less tumorigenic capacity compared with cells from KCM tumors. Therefore, mice with KCKO tumors had a significant survival benefit compared with mice with KCM tumors. In vitro, KCKO cells have reduced proliferation and invasion and failed to respond to epidermal growth factor, platelet-derived growth factor, or matrix metalloproteinase 9. Further, significantly less KCKO cells entered the G(2)-M phase of the cell cycle compared with the KCM cells. Proteomics and Western blotting analysis revealed a complete loss of cdc-25c expression, phosphorylation of mitogen-activated protein kinase (MAPK), as well as a significant decrease in nestin and tubulin-α2 chain expression in KCKO cells. Treatment with a MEK1/2 inhibitor, U0126, abrogated the enhanced proliferation of the KCM cells but had minimal effect on KCKO cells, suggesting that MUC1 is necessary for MAPK activity and oncogenic signaling. This is the first study to utilize a Muc1-null PDA mouse to fully elucidate the oncogenic role of MUC1, both in vivo and in vitro.
Assuntos
Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Mucina-1/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Animais , Butadienos/farmacologia , Carcinoma Ductal Pancreático/enzimologia , Ciclo Celular/fisiologia , Processos de Crescimento Celular/fisiologia , Fator de Crescimento Epidérmico , Humanos , Proteínas de Filamentos Intermediários/biossíntese , Metaloproteinase 9 da Matriz , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mucina-1/genética , Metástase Neoplásica , Proteínas do Tecido Nervoso/biossíntese , Nestina , Nitrilas/farmacologia , Neoplasias Pancreáticas/enzimologia , Fator de Crescimento Derivado de Plaquetas , Inibidores de Proteínas Quinases/farmacologia , Tubulina (Proteína)/biossínteseRESUMO
The obesity epidemic is spreading to low-income and middle-income countries as a result of new dietary habits and sedentary ways of life, fuelling chronic diseases and premature mortality. In this report we present an assessment of public health strategies designed to tackle behavioural risk factors for chronic diseases that are closely linked with obesity, including aspects of diet and physical inactivity, in Brazil, China, India, Mexico, Russia, and South Africa. England was included for comparative purposes. Several population-based prevention policies can be expected to generate substantial health gains while entirely or largely paying for themselves through future reductions of health-care expenditures. These strategies include health information and communication strategies that improve population awareness about the benefits of healthy eating and physical activity; fiscal measures that increase the price of unhealthy food content or reduce the cost of healthy foods rich in fibre; and regulatory measures that improve nutritional information or restrict the marketing of unhealthy foods to children. A package of measures for the prevention of chronic diseases would deliver substantial health gains, with a very favourable cost-effectiveness profile.
Assuntos
Doença Crônica/prevenção & controle , Dieta/economia , Promoção da Saúde/economia , Estilo de Vida , Obesidade/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , China/epidemiologia , Doença Crônica/economia , Análise Custo-Benefício , Dieta/efeitos adversos , Exercício Físico , Alimentos/economia , Gastos em Saúde , Humanos , Índia/epidemiologia , México/epidemiologia , Pessoa de Meia-Idade , Modelos Teóricos , Obesidade/complicações , Obesidade/epidemiologia , Anos de Vida Ajustados por Qualidade de Vida , Fatores de Risco , Federação Russa/epidemiologia , África do Sul/epidemiologiaAssuntos
Biomassa , Biotecnologia/métodos , Hidrólise , Celulose/química , Lignina/química , SolventesRESUMO
Recent research work in-house both at Auburn University and National Renewable Energy Laboratory has demonstrated that extremely low concentrations of acid (e.g., 0.05-0.2 wt% sulfuric acid) and high temperatures (e.g., 200-230 degrees C) are reaction conditions that can be effectively applied for hydrolysis of the cellulosic component of biomass. These conditions are far from those of the conventional dilute-acid hydrolysis processes, and the kinetic data for glucose decomposition are not currently available. We investigated the kinetics of glucose decomposition covering pH values of 1.5-2.2 and temperatures of 180-230 degrees C using glass ampoule reactors. The primary factors controlling glucose decomposition are the reaction medium, acid concentration, and temperature. Based on the experimental data, a kinetic model was developed and the best-fit kinetic parameters were determined. However, a consistent discrepancy in the rate of glucose disappearance was found between that of the model based on pure glucose data and that observed during the actual process of lignocellulosic biomass hydrolysis. This was taken as an indication that glucose recombines with acid-soluble lignin during the hydrolysis process, and this conclusion was incorporated accordingly into the overall model of glucose decomposition.